let's talk hallucination

[thujone]

to the best of my understanding, hallucinations are caused by chemicals binding to 5-ht receptors.

but in order to do so, psychoactive drugs will first need to hitch a ride on specific transporter proteins to bind with the 5-ht receptors (in the g protein-coupled receptor group?) which are most noted for their reuptake of serotonin.

now, bear with me for another moment: serotonin agonists bind to the 5-ht receptors to cause more serotonin hangtime in the synaptic cleft which results in us feeling the effects of the increased serotonin, right?

in that case, are chemicals left in the synaptic cleft responsible for part of the hallucinatory effect, or are serotonin, norepinephrine, dopamine and epinephrine merely a powerful adjunct to post-synaptic occurences caused by psychoactive drugs binding to the 5-ht receptors? in other words; are the hallucinatory effects caused simply by where LSD-25 (for example) crosses wires post-synaptically or does the presence of serotonin in the synaptic cleft also lend to hallucinations?

i would really like to get my head around this, though the information available is somewhat limited. perhaps it's because of the taboo nature of hallucinogenic compounds in the professional world that such topics aren't explored to the fullest of their potential. either way, if someone can guide me to answers it would be much appreciated

 

[Jamshyd]

to the best of my understanding, hallucinations are caused by chemicals binding to 5-ht receptors.

It really depends on what you mean by "hallucinations" since this term is very open to interpretation. Paranoid people "hallucinate", people who are tripping "hallucinate", and people on shopping sprees also "hallucinate". I do assume you are referring to classic psychedelic visuals, though.

but in order to do so, psychoactive drugs will first need to hitch a ride on specific transporter proteins to bind with the 5-ht receptors (in the g protein-coupled receptor group?) which are most noted for their reuptake of serotonin.

Serotonin is not necessarily what is directly responsible for this, although neuronal systems/currents (that happen to be serotonergic) seem to be the cause through over-excitement that is interpreted as sensory phenomena. This is my understanding anyway, and I am open for corrections...

now, bear with me for another moment: serotonin agonists bind to the 5-ht receptors to cause more serotonin hangtime in the synaptic cleft which results in us feeling the effects of the increased serotonin, right?

And just what are the effects of "increased serotonin"? Correlation does not imply causation...

or are serotonin, norepinephrine, dopamine and epinephrine merely a powerful adjunct to post-synaptic occurences caused by psychoactive drugs binding to the 5-ht receptors? in other words; are the hallucinatory effects caused simply by where LSD-25 (for example) crosses wires post-synaptically or does the presence of serotonin in the synaptic cleft also lend to hallucinations?

I am of the opinion that it is the latter, and that the change in monoamine levels is merely a side-effect (or an intermediate effect). I tend to discourage looking at macro-phenomena such as visuals on the micro-scale that is monoamines. It probably has more to do with electric currents inside big chunks of the brain than a few molecules in the synapse.

i would really like to get my head around this, though the information available is somewhat limited. perhaps it's because of the taboo nature of hallucinogenic compounds in the professional world that such topics aren't explored to the fullest of their potential. either way, if someone can guide me to answers it would be much appreciated

I think the main problem here is that you're focusing way too much on the specifics and ignoring the big picture, although I don't blame you since this has been neuro orthodoxy until recently.

 

[Ham-milton]

serotonin agonists bind to the 5-ht receptors to cause more serotonin hangtime in the synaptic cleft which results in us feeling the effects of the increased serotonin, right?

Ummm... No, I don't think so. That's way off from my understanding.

The agonists are binding and agonism itself is responsible for the 'hallucinations' for lack of a better term here.

LSD itself is a partial agonist at 5HT2a sites, so it's not going to be increasing the effect of SE at all, instead, it'll act as a competitive antagonist in that respect; same with DOI.

I am of the opinion that it is the latter, and that the change in monoamine levels is merely a side-effect (or an intermediate effect). I tend to discourage looking at macro-phenomena such as visuals on the micro-scale that is monoamines. It probably has more to do with electric currents inside big chunks of the brain than a few molecules in the synapse.

completely agreed.

 

[theWorldWithin]

I am no pharmacologist but my own theory always focused on the inhibitory nature of 5HT. Since a hallucinogenic compound binds to 5HT receptors but has a lower action potential it stops serotonin from doing its job of keeping the brains signaling in check. You mind is in a "run away" mode if you will. Then the action of monoamines, specifically increased dopamine is the actual source of hallucinations.

This would make a decent amount of sense since a drug like MDMA which cause massive amounts of 5HT release do not cause hallucinations to any serious degree despite large amounts of monoamine release/reuptake inhibition. The hallucinations are absent because 5-HT is doing its job of keeping the brain in check. Also all drugs with significant effects on dopamine will cause hallucination similar but not identical to 5HT agongists, think high dose amphetamines and opiates.

My theory may be way way off the mark but I think it is ridiculous to say that the effects of monoamines are a trickle down side effect of 5HT agonism. Clearly the amount and nature of monoamine and cholinergic activity is key in the specifics of hallucinations. This can be infered by the greater depth of experience on highly promiscuious compounds such as LSD which hits an outrageous diversity of receptor sites.

 

[Jamshyd]

^ Actually, your idea is not far from my understanding of the action of dissociatives, in that the inhibition of sensory input causes the brain to "fill in the blanks" caused by blocked sensory data.

This is not true for serotonergic psychedelics though, as their effects are definitely attributed to their excitatory action.

 

[swilow]

^Isn't agonism of 5HT recpetors simply inhibiting their ability to transport informtion, normally? I mean, agonism refers to decresing the action-potential of the neuron yes? So, by blocking the effects of seratonin in certain pathways, which effect emotion and vision and (yeah everything), the brain begins feedback processing to maintain a stable reality or sort.

I think that by inhibitng seratonin in certain regions must be responslible for the downstream glutaminergic effects of say, LSD.

Dissociatives seem to split my sense into seperate, consious entites rather then dislocate me from them.

 

[Jamshyd]

^Isn't agonism of 5HT recpetors simply inhibiting their ability to transport informtion, normally? I mean, agonism refers to decresing the action-potential of the neuron yes? So, by blocking the effects of seratonin in certain pathways, which effect emotion and vision and (yeah everything), the brain begins feedback processing to maintain a stable reality or sort.

Not necessarily - it seems to depend on what subtype of 5-HT receptor we're talking about. Some of these receptors have an excitatory action.

I think that by inhibitng seratonin in certain regions must be responslible for the downstream glutaminergic effects of say, LSD.

I don't know if this is even possible, since glutamate will always "override" serotonin in that glutamate receptors are ion channels within themselves and therefore have a more direct action than 5-HT receptors.

I could be wrong here, but I am thoroughly convinced that studying monoamines will not give much insight into psychic phenomena, just as studying quantum mechanics doesn't give much insight into social phenomena, even though it is a pertinent part of them.

Dissociatives seem to split my sense into seperate, consious entites rather then dislocate me from them.

Ah, but see, that is your own perception of dissociative anaesthesia . The fact remains that these particular sensations/perceptions are caused through the blockade of normal sensory transmission.

 

[swilow]

I don't know if this is even possible, since glutamate will always "override" serotonin in that glutamate receptors are ion channels within themselves and therefore have a more direct action than 5-HT receptors.

Well, it does happen, though perhaps prior to the intoxication. LSD was probably a bad example.

 

[theWorldWithin]

Not necessarily - it seems to depend on what subtype of 5-HT receptor we're talking about. Some of these receptors have an excitatory action.

Then why does MDMA have such a sedating quality to it? I was under the impression that most 5-HT receptors played an inhibitory role. Serotongenic psychs are better at fitting into the receptor but less effective at activating its inhibitory role, thus haveing a net effect of disinhibition. This disinhibition allows the monoamines effect to manifest itself in big ways in your consciousness.

With its connection to psychosis, pleasure, and stimulation I speculate that dopamine is what is actually causing most of these effects because 5-HT is no longer keeping it in check. In my mind the monoamines are the most important part of the psychedelic equation. But I do not have anywhere near the amount of education on the subject that many of you do.

I still find it so curious that MDMA is hardly psychedelic and quite sedating yet LSD is full on balls to the wall with tons of stimulation. Both act so dramatically on serotongenic systems but result in opposite effects. To me this points to 5-HT having a mostly inhibitory action. Then again methamphetamine releases large amounts of 5-HT but can be quite psychedelic when taken orally. Perhaps it really comes down to what region of the brain is affected by these compounds, in LSD's case this is obvious. I am not well educated on the brain regions affected by MDMA and MA. Maybe looking to the realtionships between different psychs and amphetamines is not a valid analogy for discovering the root cause of hallucinations on the micro scale.

 

[MurphyClox]

Then why does MDMA have such a sedating quality to it? I was under the impression that most 5-HT receptors played an inhibitory role. Serotongenic psychs are better at fitting into the receptor but less effective at activating its inhibitory role, thus haveing a net effect of disinhibition. This disinhibition allows the monoamines effect to manifest itself in big ways in your consciousness.

With its connection to psychosis, pleasure, and stimulation I speculate that dopamine is what is actually causing most of these effects because 5-HT is no longer keeping it in check. In my mind the monoamines are the most important part of the psychedelic equation. But I do not have anywhere near the amount of education on the subject that many of you do.

I still find it so curious that MDMA is hardly psychedelic and quite sedating yet LSD is full on balls to the wall with tons of stimulation. Both act so dramatically on serotongenic systems but result in opposite effects. To me this points to 5-HT having a mostly inhibitory action. Then again methamphetamine releases large amounts of 5-HT but can be quite psychedelic when taken orally. Perhaps it really comes down to what region of the brain is affected by these compounds, in LSD's case this is obvious. I am not well educated on the brain regions affected by MDMA and MA. Maybe looking to the realtionships between different psychs and amphetamines is not a valid analogy for discovering the root cause of hallucinations on the micro scale.

MDMA sedating?! MDMA is hardly a psychedelic? It's hardly a hallucinogen but it's THE psychedelic and everything else than sedating at all.
Who is confused? You or me? :D 8)

 

[Jamshyd]

Then why does MDMA have such a sedating quality to it? I was under the impression that most 5-HT receptors played an inhibitory role. Serotongenic psychs are better at fitting into the receptor but less effective at activating its inhibitory role, thus haveing a net effect of disinhibition. This disinhibition allows the monoamines effect to manifest itself in big ways in your consciousness.

See, here is another example of why looking at a few molecules within a single synapse at a single moment will never give you answers to psychic phenomena. A single neuron being excited hardly translates into a perception of a stimulated state of mind. [

With its connection to psychosis, pleasure, and stimulation I speculate that dopamine is what is actually causing most of these effects because 5-HT is no longer keeping it in check. In my mind the monoamines are the most important part of the psychedelic equation. But I do not have anywhere near the amount of education on the subject that many of you do.

The "dopamine connection" has always been a disputed one, and, fortunately, science is now starting to move away from trying real hard to find "silver-bullet" answers to complex (emergent) states of mind. I do not claim to know more than you do, but I'm simply repeating what I read and what makes sense to me.

I still find it so curious that MDMA is hardly psychedelic and quite sedating yet LSD is full on balls to the wall with tons of stimulation. Both act so dramatically on serotongenic systems but result in opposite effects. To me this points to 5-HT having a mostly inhibitory action. Then again methamphetamine releases large amounts of 5-HT but can be quite psychedelic when taken orally. Perhaps it really comes down to what region of the brain is affected by these compounds, in LSD's case this is obvious. I am not well educated on the brain regions affected by MDMA and MA. Maybe looking to the realtionships between different psychs and amphetamines is not a valid analogy for discovering the root cause of hallucinations on the micro scale.

See, here you needed to resort to reporting subjective effects, which have absolutely nothing to do with the empirical findings about monoamines

 

[thujone]

now im even more confused so the drugs themselves aren't what directly cause the hallucination then but the everpresent chemicals trying to find other pathways? but what other path could serotonin choose if some other drug has completely overtaken the transport proteins?

 

[Jamshyd]

^ You're still thinking in terms of single synapses or single neurotransmitters/transporters. My point is that this level of analysis will never give you answers to questions about things like hallucinations. Hallucinations can only be explained on the level of whole-organs and signal-pathways in the brain. It has more to do with voltage levels than it has with serotonin or dopamine...etc.. These emergent phenomena can only be explained through the "bigger" picture.

The levels of neurotransmitters at the synaptic level are in a constant state of flux. A change in flux is still flux - there isn't much insight to be gained at this level.

Then again, I might be wrong.

There was a discussion about this in a thread here a couple of months ago, I forget which thread it was, but I'll try to find it for you...

EDIT: here we go... scroll down a few posts (starting at post 15): http://www.bluelight.ru/vb/showthread.php?t=370953

 

[Ham-milton]

The drug definitely causes the hallucinations, but it's not a direct effect of the drug on the receptor site. There are widespread changes induced in brain functioning that cause the change in thinking and visual phenomenon induced by disruptive signalling of receptors all over the brain- and it's not a uniform thing either, there are local hot spots of disregulation which likely play a strong role in the actual creation of visuals.

 

[swilow]

^ You're still thinking in terms of single synapses or single neurotransmitters/transporters. My point is that this level of analysis will never give you answers to questions about things like hallucinations. Hallucinations can only be explained on the level of whole-organs and signal-pathways in the brain. It has more to do with voltage levels than it has with serotonin or dopamine...etc.. These emergent phenomena can only be explained through the "bigger" picture.

Yes, but volatge levels etc. are inhibited/stimulated by the neurotransmitters seratonin and dopamine, meaning that if you don't first look at the micro picture, the macro will never make sense. The human brain can compensate for most of its functionality through using different areas of it....so when seratonin and thus voltage trasnmission is inhibited at the 5HT2a receptor, "other stuff" happens as the brain comepnsates for this negligence...but, its the "wrong stuff". IE. hallucincations. Perhaps the displaced seratonin also has psychedelic effect on some level...it could also explain the afterglow of a psychedelic experience, wherein the displaced, excess seratonin is reuptaken...and the dysphoria of the come-up on some psychedelics.

Then again, i think it was called BOL-148 (check LSD:My problem child), which has as strong a binding affinity as LSD with 5HT receptrors, but has no psychedelic effect. So- all this could be completely wrong.

I mean, why does DOB enter the lungs before becomning halluncinogenic?

 

[Ham-milton]

BOL-148 is a selective 5HT2a antagonist, it's not really relevant here, and DOB seems to be a prodrug, but I can't find confirmation or denial of that.

It may just be that the lungs issue is a red herring. Levels build up in the lungs first and then only goes up into the brain after the levels reach a certain point. It could just be

Yes, but volatge levels etc. are inhibited/stimulated by the neurotransmitters seratonin and dopamine, meaning that if you don't first look at the micro picture, the macro will never make sense.

Sure, you need to know that receptors are being agonised by a different substance than what they usually encounter, and that they're disrupting the system, but it's not what happens at individual receptors that's causing the hallucinations. The agonism is producing a different effect than usual, but that itself doesn't seem to be what's causing the hallucinations directly.

It seems that it's the general disregulation going on generally and locally that's causing the hallucinations.

The human brain can compensate for most of its functionality through using different areas of it....so when seratonin and thus voltage trasnmission is inhibited at the 5HT2a receptor, "other stuff" happens as the brain comepnsates for this negligence...but, its the "wrong stuff". IE. hallucincations.

agreed

Perhaps the displaced seratonin also has psychedelic effect on some level...it could also explain the afterglow of a psychedelic experience, wherein the displaced, excess seratonin is reuptaken...and the dysphoria of the come-up on some psychedelics.

There's no displaced or excess serotonin. Serotonin is still being released, binding and being taken back up. I don't know of any research showing that the release or uptake is inhibited by 5HT2a drugs.

In the presense of LSD and the other partial agonist ligands, serotonin will be prevented from binding or pushed out of the receptor by LSD if it's already in it, so in this respect, there is displaced (but still not extra) serotonin.

However, that's entirely irrelevant here because we have other full agonist 5HT2a ligands that produce the same effects.

What you're suggesting would mean that if we were to apply a 5HT2a antagonist that after it wore off, and the serotonin would be able to bind there again we'd experience a psychedelic effect or at least an "after-glow"- but that's not the case.

 

[pofacedhoe]

seems that serotonin is inhibitory in monoamine terms and lsd, mescaline, etc. have their effects by preventing the effect of serotonin on certain neural networks allowing many that normally are not switched on simulanteously to be on at once. this results in sensory overload and a lack of inhibitory filtering that would normally occur. this lack of normal flitering results in hallucinations (or "false positives").

people with mental problems often lack the ability to correctly fliter out useless sensory overload information, and those who have taken drugs with way too much dopamine effect (meth/speed) will hallucinate as this overpowers the serotonin inhibition.

lack of inhibition on a micro level will, on larger brain stytems, cause inhibitory pathways to not inhibit signals which lead parts of the brain organ to interact without the inhibiton that places a priority on the importance of the information from each area (frontal cortex) and synchs this info into a coherent (or not in this case) experience of perception. this means that too much info overloads and nothing is discarded by higher prioritising (on a micro/macro level)

 

[Ham-milton]

people with mental problems often lack the ability to correctly fliter out useless sensory overload information, and those who have taken drugs with way too much dopamine effect (meth/speed) will hallucinate as this overpowers the serotonin inhibition.

Absolutely backwards- and entirely irrelevant. Dopaminergics result in 'true' hallucinations, not the serotonergic type (and thus have an entirely different cause). This occurs at the end of a binge, not at the beginning when there is too much dopamine- at the end there's not enough.

If serotonin's agonism at the receptor site is inhibitory, then the same must be for the other agonists- it's not the case that two agonists at the same site produce vastly different effects (ie, inhibition vs. excitation). Whatever the cause of the 'hallucinations' is, it's the result of very small differences in agonism of the 5HT2a sites.

 

[vecktor]

The current best theory of psychedelic action, which is backed up by some good evidence is that the main action is through the 5-HT2A receptor (2AR), all these drugs bind to 2AR, the potencies of the active compounds correspond quite closely with their binding affinity and the effects can be reversed using a selective 2A antagonist. however 2AR agonism isn't everything...most psychedelics bind other 5HT receptors, tryptamines for example bind to 5HT1 and 5HT2B receptors with a higher affinity than 2AR. indeed I believe the subjective differences in feeling between phenethylamines and tryptamines may be to do with 5HT1a activation, they both activate 2ar. 5ht1a activation alone is not enough to give psychedelic effects, even though DMT has 100 times higher affinity for 1a than 2a!!

The pharmacology of some psychedelics is further confused by the ability of some of them to block monoamine uptake and cause mono-amine release though it is not known for certain how, here I am talking about the 2-CT series, however most phenthylamines psychedelics can't do this. (before someone points out the blindingly obvious, I am not talking about MDMA or other entactogens which are another family entirely with different molecular targets.)

There is no need to involve serotonin directly in psychedelic action, indeed it seems likely that the psychedelics activate the 5ht2a receptor in a way that is different to serotonin. psychedelics don't need to block serotonin, antagonists that inhibit serotonin binding and action are not psychedelic.

When psychedelics bind to the 2AR they change its shape into a form that is able to couple and activate G protein that leads eventually enhanced Arachidonic Acid production (the PLA2 pathway). whereas it seems that with non psychedelic substances even those agonists that bind very well to the 2AR do not activate the PLA2 pathway, lisuride is a very potent 5HT2A agonist measure using IP turnover, but is not anywhere near as psychedelic as LSD if it ever is at any dose.
this might be the source of some of the problems with older work done on psychedelics, it is not necessarily the case that all neurons bearing 2AR respond in the same way to psychedelics and studies where Inositol Phosphate turnover is used as a marker of agonism has the problem that non psychedelic 2AR agonists can trigger this pathway, LSD for example appears fairly poor at turning over IP. It is also worth remembering that neurons with 5HT2a receptors also have glutamate and other receptors and that most of the quick data transmission is not through serotonin, 5-ht2a does not gate an ion channel so cannot act quickly to alter a neurons behavior, rather it acts more slowly to through chemical second messengers.

enough of the molecular biology,
It seems that hallucinogenic effect comes from the compounds activating a very small population of neurons in the pre-frontal cortex. and as this area of the brain is involved in supressing and gating of inputs it seems likely that the effects of halucinogens is to reduce the gating effect allowing inputs that would otherwise be screened out to get though. causing the flooding experience, as well as the lack of 'focus' and the fact that contradicting info can get through which otherwise would be screened out by the sanity checking circuits of the brain. so to put it simply psychedlics allow noise created by random firing of neurons and other stuff through which would be stopped. they perhaps allow the conscious mind to see the raw un-processed information, the world as our eyes actually see it.

The after glow effect seems to have more do with a general shaking up of brain activity patterns, I am sure that ECT causes an after glow

There are some interesting experiments to be done some time in humans, involving specific antagonists, in particular the use of 5ht1a antagonists, combined with tryptamines to see what effect that has subjectively, I suspect it will make them feel like phenethylamines. Also it would be very interesting to see what effect blocking 5ht2c has when combined with phenethylamines. none of these studies seem likely to make it through the ethics committee barrier at the moment. still much to learn and unfortunately rats can't write trip reports.

fairly heavy but worth reading if you can access them:

Fantegrossi et al
Biochemical Pharmacology 75 (2008.) Pages 17-33 which is bigger picture macro stuff, which also has some evidence that contradicts some of the assumptions in the current theory.

and

Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior .

Neuron , Volume 53 , Issue 3 , Pages 439 - 452

 

[Ham-milton]

requested at blacklight, hopefully someone wonderful (ie, murphy!) has access to them.